Alzheimer's disease (AD) is a progressive neurodegenerative disease resulting in senile dementia. AD is the most common form of dementia. See generally Selkoe, TINS 16, 403-409 (1993); Hardy et al., WO 92/13069; Selkoe, J. Neuropathol. Exp. Neurol. 53, 438-447 (1994); Duff et al., Nature 373, 476-477 (1995); Games et al., Nature 373, 523 (1995). In general, the disease falls into two categories: late onset, which occurs in old age (65+ years) and early onset, which develops well before the senile period, i.e., between 35 and 60 years. In both types of disease, the pathology is the same but the A. beta peptide abnormalities tend to be more severe and widespread in cases where the AD symptoms begin at an earlier age, sometimes as early as the fourth decade of life. The disease is characterized by two types of lesions in the brain, senile plaques, composed mainly by aggregated long form of beta amyloid peptide, 39-42 amino acids, and neurofibrillary tangles, composed of phosphorylated cytoskeletal protein named tau. Senile plaques are areas of disorganized neuropil up to 150 μn across with extracellular amyloid deposits at the center visible by microscopic analysis of sections of brain tissue. Neurofibrillary tangles are intracellular deposits of tau protein consisting of two filaments twisted about each other in pairs.
A. beta peptide (also referred to herein as A. beta, Aβ, Aβ peptide, or amyloid beta peptide) is an internal fragment of 39-43 amino acids of a precursor protein termed amyloid precursor protein (APP). Several mutations within the APP protein have been correlated with the presence of Alzheimer's disease. See, e.g., Goate et al., Nature 349, 704) (1991) (valine.sup.717 to isoleucine); Chartier Harlan et al. Nature 353, 844 (1991)) (valine.sup.717 to glycine); Murrell et al., Science 254, 97 (1991) (valine.sup.717 to phenylalanine); Mullan et al., Nature Genet. 1, 345 (1992) (a double mutation changing lysine.sup.595-methionine.sup.596 to asparagine.sup.595-leucine.sup.596). Such mutations are thought to cause Alzheimer's disease by increased or altered processing of APP to A. beta, particularly processing of APP to increased amounts of the long form of A. beta (i.e., A. beta1-42 and A. beta1-43). Mutations in other genes, such as the presenilin genes, PS1 and PS2, are thought indirectly to affect processing of APP to generate increased amounts of long form A. beta (see Hardy, TINS 20, 154 (1997)). These observations indicate that A. beta, and particularly its long form, is at least one of the causative elements in Alzheimer's disease.
In early discoveries, McMichael, EP 526,511, proposed administration of homeopathic dosages (less than or equal to 10.sup.-2 mg/day) of A. beta to patients with pre-established AD. In a typical human with about 5 liters of plasma, even the upper limit of this dosage would typically be expected to generate a concentration of no more than 2 pg/ml. The normal concentration of A. beta in human plasma is typically in the range of 50-200 pg/ml (Seubert, Vigo-Pelfrey et al., Nature 359, 325-327 (1992)).
Schenk et al, Nature, 1999 demonstrated that administration of the aggregated form of beta amyloid peptide with 42 amino acids reversed the AD pathology in the brain of transgenic mice. Their similar experiments later conducted in humans however, resulted in an encephalitic-like inflammatory reaction in the brain of these patients resulting in death in some of them. This inflammatory reaction has been attributed to a Th2 immunoreaction. The clinical studies were immediately stopped and other forms of immunization are being tested, particularly using various kinds of antibodies that recognize particular epitopes of the amyloid beta peptide.
Sphingosine-1-phosphate (S1P) is present in blood plasma and is one of the most potent growth factors displaying proangiogenic properties, (Pilorget et al, Journal of Cerebral Blood Flow & Metabolism, 2005). S1P has been shown to act as an intracellular and extracellular messenger in the nervous system (Anelli et al, J. of Neurochemistry, 2005), to control proliferation, survival, differentiation and prevent apoptosis in neural cells, thereby regulating neural signaling and function (Colombaioni, Garcia-Gil, Brain Research Reviews, 2004, Saba and Hla, Circulation Research, 2007). S1P also controls migration of neuronal stem cells toward a site of spinal cord injury, thereby suggesting that S1P has a therapeutic potential as a regenerative agent in the nervous system (Kimura et al, Stem Cells, 2007).
From all these observations, we have concluded that S1P in combination with A. beta peptide administered in a liposomal formulation or even with other non-liposomal adjuvant would improve the therapeutic or prophylactic effects of amyloid beta peptide seen before, while preventing apoptosis and inflammation and inducing neuronal repair and survival. The liposomal formulation used as adjuvant, not only incorporates S1P and A. beta peptide into the bilayer, but also preserves the structure of A. beta peptide which in combination with S1P should prevent the inflammatory reactions observed in previous AD vaccines using A. beta peptide alone.
Thus, in certain preferred embodiments the present invention is directed to treatment of Alzheimer's and other amyloidogenic diseases by administration of A. beta peptide 42 and S1P integrated in a liposomal configuration, herein called EB101, to a patient under conditions that generate a beneficial immune response in the patient while preventing inflammation and stimulating neuronal repair and regeneration. The invention thus fulfills a longstanding need for therapeutic regimes for preventing or ameliorating the neuropathology of AD and other amyloidogenic diseases.